The civilian chemical threat spectrum, including chemical warfare agents, toxic industrial chemicals and agricultural chemicals exposes millions of people to risk of morbidity and mortality every day. The development of countermeasures to mitigate mass casualty risk by intentional or unintentional dissemination of chemical threats is of critical importance, and many of these threats have devastating effects on cellular respiration. proposed project aims to provide a therapeutic intervention for mitochondrial and metabolic inhibition by The supplying an alternative source of energy that can bypass inhibition of complex I (CI) of the electron transport chain. Such a therapeutic would mitigate the toxic effects of a wide range of chemical agents that directly or indirectly inhibit cellular respiration. As added innovation, this proposal will continue development of human mitochondrial assays for testing toxicity and pharmaceutical interventions program for the development of future compounds targeting inhibition of cellular respiration a platform of great value for the CounterACT and NIH Biodefense. Our preliminary data show that cell-permeable succinate can improve respiration in cells with impaired CI function due to rotenone exposure, a toxin known to inhibit CI. Given this promising data, we propose to investigate whether cell-permeable succinate given after a toxic exposure will improve chemically induced metabolic and mitochondrial dysfunction. Furthermore, we hypothesize that this therapeutic can be used to treat a wide range of clinically relevant chemical agents by supporting mitochondrial function. We aim to characterize the toxic effects on mitochondria using human blood cells collected from volunteers in vitro and in vivo rodent models and to evaluate cell-permeable succinate as a treatment. Specific Aim 1. Determine in vitro effects on mitochondrial function of selected chemical agents in human cells, and assess the capability of cell-permeable succinate prodrugs to attenuate toxic effects. Specific Aim 2. Determine the efficacy of cell-permeable succinate prodrugs using in vivo models of mitochondrial dysfunction and reduced cellular respiration due to chemical exposure.